Bisdichloroacetyldiamines such as WIN 18,446 function as oral, reversible, non-hormonal male contraceptives by inhibiting testicular retinoic acid biosynthesis and, subsequently, spermatogenesis. Retinoic acid is produced in the germ cells by the enzymes aldehyde dehydrogenase-1A1 and 1A2 (ALDH1A1/1A2), which are potently inhibited by WIN 18,446. Unfortunately, WIN 18,446 also inhibits aldehyde dehydrogenase-2, leading to disulfiram reactions when administration of WIN 18,446 is combined with alcohol. In this proposal, we will develop novel specific inhibitors of ALDH1A1/1A2 that can exert contraceptive effects without inhibiting ALDH2. We have developed several potent and specific inhibitors of ALDH1A1/1A2, and tested them extensively in vitro and in vivo. The two current lead scaffolds are selective for ALDH1A1/1A2 with IC50s of <200 nM and do not inhibit ALDH2. However, they are currently not as effective as BDADs at suppressing spermatogenesis due to sub-optimal pharmaceutical properties. In Aims #1 of this proposal, we will optimize the potency, selectivity, solubility and pharmaceutical characteristics of our inhibitors using computer-guided chemical modifications based upon the our recently solved X-ray co-crystallographic structure of the inhibitors in the ALDH1A substrate binding site. In Aim #2 we will conduct in vitro testing (solubility, absorption and metabolism) and in vivo pharmacokinetic and pharmacodynamic studies to determine the best inhibitor for testing as a male contraceptive. In Aim #3 of this proposal, we will test the ability of the most promising inhibitors to suppress spermatogenesis and fertility in mice. If successful, the proposed experiments will result in novel specific inhibitors of ALDH1A1/1A2 for male contraception and lead to an effective, oral, non-hormonal male contraceptive, finally bringing the dream of a ?male pill? to fruition.